Bioinspired closed-loop deep brain stimulation for disorders of decision-making

历史上，帕金森病（PD）被定义为一种运动障碍。然而，越来越清楚的是，神经精神症状的发生是潜在疾病及其治疗的结果。例如，丘脑下核深部脑刺激（STN-DBS）与冲动控制失调有关，导致冲动和强迫行为（ICBs）。实验1在高冲突决策过程中，STN在反应抑制中起关键作用，这被认为是通过内侧前额叶皮层（mPFC）和STN的θ波段（4-8Hz）耦合发生的。在治疗频率（60-150Hz）下，STN-DBS破坏了mPFC-STN耦合，减少了反应时间，增加了高冲突决策的错误率。为了验证行为的电生理相关性可以为刺激范式提供信息的假设，以及这些电生理特征编码调节行为的大脑区域之间的双向通信，我将进行theta频率STN-DBS的研究。先前的研究已经证明了这种方法的安全性，但尚未对全脑网络效应进行调查。在高冲突决策任务中，将招募有或没有ICBs的PD患者，这些患者已内化了STN-DBS植入物，并将其纳入高频STN-DBS试验。将行为结果与治疗频率的STN-DBS和STN-DBS进行比较。同时进行电生理记录（MEG/EEG）以确定任务期间的mPFC theta-coherence，全脑建模管道将确定更广泛的决策网络效应。实验2在人类中，从功能磁共振成像数据中发现了一个决策行动启动网络，与非人类灵长类动物相关。值得注意的是，这些包括DBS靶点，如桥脚核。经颅超声刺激（TUS）已经证明对非人类灵长类动物的决策网络有可重复的影响，但尚未在人类身上进行测试。为了验证该决策网络中网络节点的TUS可以导致人类可重复和可逆的行为改变的假设，我将在健康志愿者和PD患者中进行一项研究，调查该网络中目标的TUS。参与者将在TUS期间使用安全参数完成高冲突决策任务，并将接受fMRI成像以检测网络调制。实验3基于观察到的结果，这些目标的一个子集将用于识别决策网络调制的电生理相关。为了验证这些网络效应是双向的并且与观察到的任务表现相关的假设，植入DBS装置的PD患者将被招募到TUS/DBS研究中。这将利用现代DBS设备的容量来记录和遥测读取内部化后的局部场电位（LFP）：第一阶段：在关键网络节点的TUS期间记录决策的LFP信号。这些LFP记录将与行为结果相关联。阶段2：相关LFP特征将用于定义增产设置。植入的DBS设备将被编程为这些设置，参与者将在没有TUS的情况下重复决策任务。行为结果将与TUS期间的结果进行比较。阶段3：这些决策的LFP特征将用于概念验证闭环刺激范例，以证明个体的可重复性。

Historically, Parkinson's disease (PD) was conceptualised as a movement disorder. However it is increasingly clear that neuropsychiatric symptoms occur both as a result of the underlying disease and its treatment. For example, subthalamic nucleus deep brain stimulation (STN-DBS) has been implicated in the dysregulation of impulse control, leading to impulsive and compulsive behaviours (ICBs). Experiment 1 The STN is pivotal in response inhibition during high-conflict decision-making and this is thought to occur through theta-band (4-8Hz) coupling of the medial prefrontal cortex (mPFC) and the STN. At therapeutic frequencies (60-150Hz) STN-DBS disrupts this mPFC-STN coupling, reducing reaction time and increasing error rates in high-conflict decision-making. To test the hypothesis that electrophysiological correlates of behaviour can inform stimulation paradigms, and that these electrophysiological signatures encode bidirectional communication between brain regions that modulate behaviour, I will conduct a study of theta-frequency STN-DBS. Previous studies have demonstrated the safety of this but whole-brain network effects have not been investigated. PD patients with and without ICBs who have internalised STN-DBS implants will be recruited into a trial of theta-frequency STN-DBS during a high-conflict decision-making task. Behavioural outcomes will be compared against therapeutic-frequency STN-DBS and STN-DBS off. Simultaneous electrophysiological recordings will be taken (MEG/EEG) to identify mPFC theta-coherence during task and a whole-brain modelling pipeline will identify the wider decision-network effects.Experiment 2 In humans, a decision-making action initiation network has been identified from fMRI data, with correlates in non-human primates. Notably, these include DBS targets such as the pedunculopontine nucleus. Transcranial Ultrasound Stimulation (TUS) has demonstrated reproducible effects on this decision-making network in non-human primates but this has not yet been tested in humans. To test the hypothesis that TUS of network nodes in this decision-making network can lead to reproducible and reversible behavioural change in humans, I will conduct a study investigating TUS of targets within this network in healthy volunteers and PD patients. Participants will complete high-conflict decision-making tasks during TUS using safe parameters, and will undergo fMRI imaging to detect network modulation. Experiment 3 Based on the observed findings, a subset of these targets will be used to identify electrophysiological correlates of decision network modulation. To test the hypothesis that these network effects are bidirectional and correlate with observed task performance, PD patients with implanted DBS devices will be recruited into a TUS/DBS study. This will utilise the capacity of modern DBS devices to record and telemetrically readout local field potentials (LFPs) after internalisation: Phase 1: LFP signals of decision-making will be recorded during TUS of key network nodes. These LFP recordings will be correlated with behavioural outcomes. Phase 2: Correlated LFP signatures will be used to define stimulation settings. Implanted DBS devices will be programmed to these settings and participants will repeat the decision-making tasks without TUS. Behavioural outcomes will be compared to those during TUS. Phase 3: These LFP signatures of decision-making will be used in a proof-of-concept closed-loop stimulation paradigm to demonstrate reproducibility within individuals.